G-CSF produces shot to the heart

Sydney researchers are about to enter a Phase II trial testing whether injections of granulocyte-colony stimulating factor (G-CSF) to stimulate the release of blood vessel-forming stem cells can assist people with severe heart disease.

The trial, a joint initiative between the Victor Chang Cardiac Research Institute and St Vincent's Hospital, will involve 40 patients with refractory angina. A combination of physiotherapist-monitored exercise and G-CSF injections will be administered, followed by MRI scans to analyse how effectively the heart is operating.

"We are interested in the potential to use ... G-CSF, which is used everyday by haematologists to treat people who have malignancies such as leukaemia or who need a bone marrow transplant, to try to stimulate their bone marrow to produce more cells," Victor Chang Institute executive director, Professor Bob Graham, said.

"What was entirely unexpected was that this substance has an effect on other tissues, and in particular it seems to affect in a very beneficial way heart cells."

Graham said the particular aim of the Phase I safety trial was to see if G-CSF could stimulate the release of stem cells from the bone marrow. He said it was known that in addition to causing more cells to be created, G-CSF also causes their release into the bloodstream.

"So we wanted to see if we could give this compound, increase the number of cells into the circulation and then see if we could harvest those cells and put them ... into the coronary artery to try to direct them to the heart and make new blood vessels," he said. "And that would help to relieve the pain because it would provide more blood flow to the heart.

"Much to our surprise we found that this whole procedure seemed to benefit the patients but interestingly they got as much benefit from the initial dose of the drug as they got from the subsequent dose when we put the cells down the coronary artery, suggesting that the drug itself may have some beneficial effect on the heart. That's what we want to try and pursue in this second study."

Co-investigator Professor Peter Macdonald, joint head of St Vincent's transplant program and professor of medicine at the University of New South Wales, said the team found a quite dramatic relief of symptoms in the patients and it may in future become an alternative for patients who would otherwise be facing a heart transplant.

"It's fair to say that at this stage we are fairly unclear exactly how this drug is producing the benefit that we observed," Macdonald said. "What we want to do in this Phase II study is explore in more detail the potential mechanisms by which this drug is working.

"One potential mechanism is that we know this drug releases stem cells from the bone marrow and those then circulate throughout the body. We know these stem cells can track to the heart [but] we don't know whether it's the stem cells that are released by the drug that are actually producing the beneficial effect of the drug, or whether it's a direct effect of the drug acting on receptors within the heart muscle cells. That's something that we need to explore in more detail in the second phase of the study."

However, it may not be entirely necessary to first stimulate the stem cells and then harvest them for injection into the coronary artery.

Graham said one of the reasons why the patients were exercised was to try to induce a lack of blood supply to see if that turns on mechanisms that allow the targeting of the stem cells to the heart.

"It may be just sufficient to do the exercise and give the G-CSF without having to collect the cells and put them down the coronary artery," Graham said.

"[That] would make things a lot simpler and what we want to try to do long term is not only to get something effective but also something that is utilisable widely by doctors in the community, not just specialists at hospitals such as St Vincent's.

"It's very important that you have practical treatments - you can have fancy treatments but if they are not applicable except at major metropolitan centres then of course the treatment is limited."

The Phase II trial, involving 40 patients, is expected to last two and a half years. St Vincent's clinical cardiology fellow Dr Sharon Chih, who will be conducting the trial, said it would combine an exercise program with G-CSF therapy.

"G-CSF is going to be administered in low doses, in repeated cycles over a long period and initially half the patients will be randomised to receive G-CSF, and the other half a placebo to serve as the control group," Chih said.

"After 12 weeks these two groups will cross over to receive the opposite therapy. Over the duration of the trial the progress will be monitored by a series of tests involving an MRI scan. This will look at blood flow to the heart as well as heart function itself."

The research is being funded by the MBF Foundation.